Contribution to the development of inhibitors of 17β-hydroxysteroid dehydrogenase types 1 and 7: key tools for studying and treating estrogen-dependent diseases.

17β-Hydroxysteroid dehydrogenases (17β-HSDs) belong to a group of key enzymes involved in the biosynthesis of steroidal hormones by catalyzing the reduction of 17-ketosteroids or the oxidation of 17β-hydroxysteroids. From three members known in the early nineties, the 17β-HSD functional family has grown to 15 members over the last 20 years. This growing number of 17β-HSD isoforms questioned the importance of each member, especially in their implication in estrogen- and androgen-dependent diseases, such as breast and prostate cancers. One of the strategies used to address the physiological importance of 17β-HSDs is to use potent and selective inhibitors. Furthermore, enzyme inhibitors could also be of therapeutic interest by reducing the level of estradiol (E2). Focusing on estrogens, we targeted 17β-HSD types 1 and 7, two enzymes able to transform the weak estrogen estrone (E1) into the potent estrogen E2. The present review article gives a description of different classes of inhibitors of 17β-HSD1 (C6-derivatives of E2, C16-derivatives of E2 as alkylating and dual action compounds, E2-adenosine hybrids, E2-simplified adenosine hybrids, and C16-derivatives of E1 or E2) and of inhibitors of 17β-HSD7, all these inhibitors developed in our laboratory. The chemical structures and inhibitory activity of these steroidal inhibitors, their potential as therapeutic agents, and their use as tools to elucidate the role of these enzymes in particular biological systems will be discussed. Article from the Special issue on Targeted Inhibitors.